Renal Replacement TherapyWhen and how much…When and how much…

M. JoannidisMedizinische Intensivstation

Universitätsklinik für Innere Medizin IMedizin Universität Innsbruck

Early vs late start of RRT

Liu et al, CJASN 2006

Initiation of CRRTafter the “millennium party”

Large (n>100), randomized trials renal replacement therapy in ICU patients with AKI endpoint - mortality

• BUN 50 mg/dl, Crea 3.5 mg/dl (Ronco C, Lancet 2000)• BUN 85 mg/dl, Crea 4.5 mg/dl (Mehta R, Kidney Int 2001)• BUN 90 mg/dl, Crea 5.0 mg/dl (Schiffl H, NEJM 2002)• BUN 83 mg/dl, Crea 4.3 mg/dl (Saudan P, Kidney Int 2006)• BUN 76 mg/dl, Crea 4.3 mg/dl (Tolwani A, JASN 2008)• BUN 66 mg/dl (ATN-VA, NEJM 2008)• BUN 63 mg/dl, Crea 3.4 mg/dl (Faulhaber-;NDT 2009)• BUN 64 mg/dl, Crea 3.4 mg/dl (RENAL, NEJM 2009)

Group 1 (late):• crea> 5mg/dl or K>5.5 mmol/l

Group 2 (early):• Uo < 100ml for 8h despite

furosemide 50mg

J Card Surgery 2004; 19:17-20

CVVHDF dose?

J Card Surgery 2004; 19:17-20

Timing of RRT in Acute Renal Failure -Meta Analysis

Seabra VF. AJKD 2008

Should we use RIFLE Criteria for initiation?

Bellomo R , Crit Care 2004

Late initiation of renal replacement therapy is associated with worse outcomes in

acute kidney injury after major abdominal surgery

RIFLE Risk however…

Shiao C-C, Crit Care 2009

further problems:•CKD 55% vs 28% p<0.008•Baseline Crea 2.1 vs 1.3 mg/dl

RIFLE Failure

Should we use RIFLE Criteria for initiation?

No association between RIFLE stage at start of CRRT and survival!survival!

Maccariello et al, Intensive Care Med 2007

RIFLE classification in patients with acutekidney injury in need of renal replacement

therapy

Maccariello et al, Intensive Care Med 2007

What are relevant paramters for initiation?

• Urea?• Creatinine?• Creatinine?• Urinary Output?• Volume overload?

„Unguided fluid administration may be hazardous….“

Fluid Management in ALIFluid balance / week

Conserv. Strategy (n=503): Liberal Strategy (n=498):

-136 (+ 491) ml + 6992 (+502) ml

ARDS Clinical Network Trial, NEJM 2006

Effect on fluid overload on survival (PICARD Study)

Mortality rate by final fluid accumulation relative tobaseline weight and stratified by dialysis status

Bouchard J et al, Kidney Int 2009610 Pat. (65% RRT), 5 Academic Centres

Start of CRRT in Start of CRRT in SEPSISSEPSIS

•• AKIAKI

•• IntubationIntubation

•• vasopressorsvasopressors

DeathDeath

•• IRVIRV

•• AKIAKI

Clinical trials -CRRT in Sepsis

• randomized trial with 24 pt. in early septic shock

• 48 h isovolemic CVVH 2L/h vs. stand. med. treatment

• 72 h observation period• 72 h observation period• primary parameters:

– C3a + C5a, interleukins 6, 8 + 10, TNF

– MODS

Cole L et al., Crit Care Med 2002

Clinical trials -CRRT in Sepsis

• randomized trial with 24 pt. in early septic shock

• 48 h isovolemic CVVH 2L/h vs. stand. med. treatment

• 72 h observation period

• No significant changes in cytokines or C3a + C5a by CVVH

• MODS – no difference between both groups.• 72 h observation period

• primary parameters: – C3a + C5a, interleukins 6, 8

+ 10, TNF– MODS

between both groups.• CVVH does not result in

improvement of oxygenation or hemodynamics

Cole L et al., Crit Care Med 2002

Clinical trials -CRRT in Sepsis

• randomized trial with 24 pt. in early septic shock

• 48 h isovolemic CVVH 2L/h vs. stand. med. treatment

• 72 h observation period

• No significant changes in cytokines or C3a + C5a by CVVH

• MODS – no difference between both groups.• 72 h observation period

• primary parameters: – C3a + C5a, interleukins 6, 8

+ 10, TNF– MODS

between both groups.• CVVH does not result in

improvement of oxygenation or hemodynamics

Cole L et al., Crit Care Med 2002

Impact of continuous venovenous hemofiltration on organ failureduring the early phase of severe sepsis.

A randomized controlled trial.

25 ml/kg/h

SEPSIS>1 organ failurewithin 24 h

Parameters at time of Randomisation:

Crea = 2.1 mg/dlBUN= 42 mg/dl

Payen D, Crit Care Med 2009

ml/kg/h (96h)

BUN= 42 mg/dlpH= 7.33UO= 1.5 l/d (~0.8 ml/kg/h)

Impact of continuous venovenous hemofiltration on organ failure during the early phase of severe sepsis.

A randomized controlled trial

Payen D, Crit Care Med 2009

Impact of continuous venovenous hemofiltration on organ failureduring the early phase of severe sepsis.

A randomized controlled trial

Payen D, Crit Care Med 2009

Early RRT …?

Consider Adverse Effects of RRT

• Loss of trace elements (e.g. selenium)• Loss of vitamines (e.g. thiamine, vit C)• Loss of vitamines (e.g. thiamine, vit C)• Loss of nutrients (AA)• Loss of heat (is cooling good for sepsis?)• Complications with catheter• Anticoagulation (e.g. heparin)

Murphy´s law

Never try to repair something that is not broken….broken….

Initiation of CRRT A worldwide practice survey (B.E.S.T kidney)

• Oliguria/anuria 70.2%

• High urea/creatinine 53.0%• High urea/creatinine 53.0%

• Metabolic acidosis 43.6%

• Fluid overload 36.7%

Uchino et al, Intensive Care Med 2007

Dose of RRT?

2007

The world of RRT

Dose of RRT2007

CVVH Daily IHDCVVH35 ml/kg/h (80%)

(Ronco C, Lancet 2000)

Daily IHDweekly KT/V 5.8

(Schiffl H, NEJM 2002)

CVVHDF42 ml/kg/h

(Saudan P, Kidney Int 2006)

Dose in RRT(Questionaire in VIcenza course of Critical Care Nephrology)

Ricci, Z. et al. Nephrol. Dial. Transplant. 2006

n=1124IHD daily or SLED orCVVHDF 35 ml/kg/h

IHD every other day or SLED or

CVVHDF 20 ml/kg/h(~22 ml/kg/h delivered)

Numbers of Patients Enrolled in the Study, Randomly Assigned to a Treatment Group, and Included in the Analysis

CVVHDF

The RENAL Replacement Therapy Study Investigators. N Engl J Med 2009;361:1627-1638

40 ml/kg/hCVVHDF 25 ml/kg/h

Dose delivered84% 88%

~33ml/kg/h ~22 ml/kg/h

Kaplan-Meier Estimates of the Probability of Death

The RENAL Replacement Therapy Study Investigators. N Engl J Med 2009;361:1627-1638

Indications:60% oliguria (<400ml/d)40-50% crea>3.4 mg/dl,BUN>70mg/dl44% severe organ edema35% acidemia

RENAL-specific aspectsHigher Intensity Lower Intensity p value

Male Age

66%64.7

64%64.4

Time in ICU before randomization

48.4 h 54.5 hrandomization

Weight Sepsis

80.8 kg49.9%

80.5 kg48.9%

Dose delivered 84%~34 ml/kg/h

88%~22 ml/kg/h

<0.001

Filters uses daily 0.93 0.84 <0.001

Hypophosphatemia 65% 54% <0.0001

CRRT Dose: how much is enough?

35

42

2025

25

30

35

40

45

Dos

e m

l/kg/

h

CVVHDFCVVH

13

20

0

5

10

15

20

25

Dos

e m

l/kg/

h

< 1999 2000 2006 2008 2009

Ron

co (

300)

Sau

dan

(200

)

AT

N (

1100

)

RE

NA

L(15

00)

DIALYSISDOSE AND SEVERITY OF DIALYSISDOSE AND SEVERITY OF DISEASEDISEASE

100100

8080high K t / Vhigh K t / V

% S

urvi

val

% S

urvi

val

6060

4040

2020

000 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

CCF ICU ARF ScoreCCF ICU ARF Score

SurvivalSurvivalaccord. CCF Scoreaccord. CCF Score

low K t / Vlow K t / V

Paganini, Am J Kidney Dis 1996Paganini, Am J Kidney Dis 1996

Should we apply a different dose in severe sepsis/septic shock?

Sepsis

CARSIL-1TNF

IL-6

PAF

endothelin

C3a/C5

Modulation of sepsis byremoval of mediators??

SIRS

CARSIL-1 IL-6

IL-10IL-2 ra

sTNFR

endothelin

Elimination (%) in Correlation toHalf-life und Elimination-coefficient

Filtrate S.C. 15 min 30 min 60 min 120min

1 l/h 0,1 0,3 0,6 1,2 2,4

1 l/h 0,25 1 2 4 8

t1/2

1 l/h 0,25 1 2 4 8

2 l/h 0,1 0,6 1,2 2,4 4,8

2 l/h 0,25 2 4 8 16

3 l/h 0,1 0,9 1,8 3,6 7,2

3 l/h 0,25 3 6 12 24

8 l/h 0,25 8 16 32 68Kierdorf H, Kidney Int 1999

Size, Kinetics und Elimination of Cytokines

Cytokine Molecular-weight (kD)

Half-life (min) Sieving-coefficient

TNF MonomerTrimer

1752

6-710-17, ~15

0-1,00-0,252 10-17, ~15 0-0,2

IL-1 18 6-10 0,07- 0,42

IL-2 ~ 10 ? 0,1-0,25

IL-6 26 6-10 0,01 – 0,32

IL-8 6-8 ~ 6 0,0 – 0,48

Kierdorf H, Kidney Int 1999

Elimination (%) in Correlation toHalf-life und Elimination-coefficient

Filtrate S.C. 15 min 30 min 60 min 120min

1 l/h 0,1 0,3 0,6 1,2 2,4

1 l/h 0,25 1 2 4 8

t1/2

1 l/h 0,25 1 2 4 8

2 l/h 0,1 0,6 1,2 2,4 4,8

2 l/h 0,25 2 4 8 16

3 l/h 0,1 0,9 1,8 3,6 7,2

3 l/h 0,25 3 6 12 24

8 l/h 0,25 8 16 32 68Kierdorf H, Kidney Int 1999

Cytokine plasma-concentrations during CVVHF

De Vriese AN, JASN 1999

Filter exchanged

CVVH UF=2L/h

Clinical trials -CRRT in Sepsis

Cole L et al., Crit Care Med 2002

The impact of long-term haemofiltration (continuousveno-venous haemofiltration) on cell-mediated

immunity during endotoxaemia

Oxidative burstSerum IL-6

Endotox Endotox

CVVH 35 ml/kg/h, porcine ETx model

Toft et al 2007, Acta Anaesthesiol Scand

Endotox

Ko

Endotox + CVVH

Endotox + CVVH

Endotox

Mortality in the Prespecified Subgroups and among All Patients

The RENAL Replacement Therapy Study Investigators. N Engl J Med 2009;361:1627-1638

Should we apply a different dose in severe sepsis/septic shock?

Summary

• Dose: 1) „individualised“ dose!2) minimal dose:

>20-25ml/kg/h CRRT>1.3 Kt/V (4h) IHD

• Inititation:

>1.3 Kt/V (4h) IHD

early:• oliguria (persistent!!)• severe organ edema• acidosis• BUN >50-80 mg% (?)

-> but not too early!

The Hannover Dialysis Outcome study: comparison of standard versus intensified extended dialysis for

treatment of patients with acute kidney injury in the intensive care unit

SLED daily (SED)BUN 60-75 mg/dl

N=76

SLED intensified (IED)BUN < 45 mg/dl

n=81

Faulhaber-Walter R, Nephrol Dial Transplant. 2009 Jul;24(7):2179-86

The VA/NIH Acute Renal Failure Trial Network

Delivered Dialysis Dose Delivered CVVHDF Dose

N Engl J Med 2008;359:7-20

Discontinuation of continuous renal replacement therapy

(B.E.S.T kidney)

436 ml/dw/o diuretics

Uchino et al, Crit Care Medicine 2009

2330 ml/dw diuretics

High-volume HF (HVH)

• 11 patients in septic shock• Design: randomized, cross-over

HVHF (8h) Standard HF (8h)HVHF (8h)

QB=300 ml/min, UF 6L/h

1,6 m² AN 69 (polyacrylonitril)

Cole L, Int. Care Med 2001

Standard HF (8h)

QB=200 ml/min, UF 1L/h

1,2 m² AN 69 (polyacrylonitril)

reductions in C3a,C5a, IL-10 (~ 80%)

reduced requirements of vasopressors

IL6 and Il1-ra in septic shock treated with HVH

• RCT: CVVH (2l/h, n=18) vs. (6l/h, n=15) over 6 h

Ghani et al, Nephrology 2006

significant reduction of IL-6 after HVH

0,6

0,8

1

Sie

ving

Coe

ffici

ent

HighFlux

High Cut-Off

HF, UF=1L/h, t=2h

Median (25th-75th percentiles)

Ex vivo Sieving Coefficients of Cytokines

0

0,2

0,4

1000 10000 100000

Sie

ving

Coe

ffici

ent

Molecular Weight [Da]

Albumin

TNFa

IL-10

IL-6

IL-1

ß2m

HighFlux

data from Uchino et al.

Pilot Study of CRRT with High Cut-off Membranes (~60kD) on the need for norepinephrine in septic Patients with acute

renal failure

Morgera S et.al , Critical Care Medicine 2006

Pilot Study of CRRT with High Cut-off Membranes (~60kD) on the need for norepinephrine in septic Patients with acute

renal failure

Morgera S et.al , Critical Care Medicine 2006

´́́́

Urea-distribution volume and total body water in critically ill patients

Ikitzler F , Kidney Int 2004Ikitzler F , Kidney Int 2004

Urea production rateCatabolic stateVolume of distribution

Timing and DosingB

UN

time

higher volume of distribution

CRRT

Timing and DosingB

UN

time

higher dose

earlier start

CRRT

Timing and DosingB

UN

time

very early start

higher dose

earlier start

volume of distribution (urea)Urea production rateCatabolic state

volume of distribution (urea)

Timing and Dosing